HENOCH-SCHÖNLEIN PURPURA
Henoch-Schönlein
purpura (HSP) is a small vessel vasculitis that can affect the skin, joints,
connective tissue, gastrointestinal tract, and kidneys. It usually affects
children who are between the ages of 3 and 15, among whom the incidence is
approximately 10 to 20 per 100,000/year. Less often, HSP may also affect
adults, generally with more severe symptoms.
HSP occurs secondary to deposition of IgA1-dominant
immune complexes in arterioles, capillaries, and venules. The pathology of the
renal lesion is indistinguishable from that seen in IgA nephropathy; indeed,
many consider the two conditions to be on the same pathogenetic spectrum, with
HSP distinguished by the presence of extrarenal involvement.
PATHOPHYSIOLOGY
The pathogenesis of HSP is largely unknown. Systemic
deposition of IgA appears to activate the alternative complement pathway. As in
IgA nephropathy (see Plate 4-16), abnormal underglycosylation of the IgA1 hinge
region appears to play a role in promoting abnormal deposition, although the
exact mechanisms remain poorly understood. As in IgA nephropathy, the renal
disease is associated with IgA binding of mesangial cells and subsequent
inflammation.
IgA1 antibodies are produced by peripheral B
lymphocytes, but the reason for their abnormal production is unclear. Case
reports have noted that HSP occurs after antecedent infections with measles, hepatitis,
varicella, group A Streptococcus, and tuberculosis, as well as after
vaccinations and insect bites. Although these findings suggest that abnormal
immune responses to common pathogens may play a role, such an association
remains speculative.
PRESENTATION AND DIAGNOSIS
The major features include palpable, nonblanching
purpura (often on the lower extremities), nonerosive oligoarthritis, renal
disease, and gastrointestinal disease. Most patients, however, do not exhibit
all four of these components.
The renal disease can include microscopic or
macroscopic hematuria, proteinuria, renal insufficiency, or a combination.
Especially in adults, the proteinuria may be severe enough to cause signs and
symptoms of the nephrotic syndrome, and acute kidney injury may also occur. The
gastrointestinal disease, which occurs secondary to submucosal edema and
hemorrhage, may be limited to pain and vomiting. Some patients, however, may
experience more significant complications, such as frank gastrointestinal
hemorrhage or intussusception. Less common systemic manifestations include
scrotal pain or swelling, as well as central nervous system disease (i.e.,
headache, seizures).
The major presenting symptoms tend to be palpable
purpura and arthritis, with gastrointestinal and renal involvement developing
in some patients over subsequent days and weeks. This sequence, however, is not
universal; in 20% to 40% of patients, for example, gastrointestinal symptoms
may precede the rash. Like-wise, 20% to 50% may have renal involvement at the initial presentation. Urinalysis may be remarkable for dysmorphic red blood cells, red blood cell casts, and
protein. Laboratory analysis of serum is generally unremarkable, although some
patients may have evidence of mild renal dysfunction. In addition, those with
more severe proteinuria may be found to have hypoalbuminemia and
hypercholesterolemia as parts of the nephrotic syndrome. Complement levels are
generally normal. Frank gastrointestinal bleeding may cause anemia, which
should be assessed using guaiac testing of stool.
Platelet counts and assays of clotting function should
be normal, which can be used to exclude other causes of purpura. IgA levels are
elevated in about half of patients but are neither sensitive nor specific for
the diagnosis of HSP.
According to current diagnostic criteria, a patient is
considered to have HSP if purpura or petechiae have a lower limb predominance,
there is no evidence of thrombocytopenia or coagulopathy, and any one of following four criteria are met: (1) abdominal pain; (2) arthritis or
arthralgia; (3) renal involvement (hematuria, proteinuria); and (4)
histopathology showing IgA dominant or codominant deposition. The diagnosis can
usually be established based on clinical indicators. When the diagnosis is uncertain
but the level of suspicion is high, a skin biopsy may be performed, which
classically reveals a leukocytoclastic vasculitis with IgA- dominant deposition
seen on immunofluorescence.
In patients with marked renal insufficiency, a renal
biopsy may be performed to determine the extent of disease and assess for the
presence of rare but serious manifestations, such as crescentic
glomerulonephritis (see Plate 4-25). The renal pathologic findings are nearly
identical to those seen in IgA nephropathy (see Plate 4-17). Using light
microscopy, mesangial hyper- cellularity is often the major feature. In more
severe cases, there may be variable amounts of endocapillary leukocyte
infiltration and cellular crescent formation, with the latter portending a
poorer prognosis. In the most severe cases, the glomerular basement membrane
may appear “split,” as in membranoproliferative glomerulonephritis (see Plate
4-22).
Immunofluorescence reveals dominant or codominant
granular staining for IgA in the mesangium and sometimes the capillary wall.
Staining for IgG and IgM may also be positive but with less intensity. The
immune deposits often colocalize with C3 but only rarely with C1q. Finally,
electron microscopy reveals electron dense deposits that correspond with the
pattern of immune complex deposition seen on immunofluorescence.
TREATMENT
Most patients experience self-limited disease that
resolves within weeks to months. During this time, treatment is mostly
supportive. Nonsteroidal anti inflammatory drugs may be given for relief of arthritis. These do not
appear to substantially increase the risk of gastrointestinal hemorrhage but
may be avoided in patients with existing hemorrhage or with poor renal function
(because of their effect on tubule glomerular feedback [see Plate 3-18]).
Unfortunately, there is a paucity of controlled trials
regarding the treatment of severe HSP. There is some evidence that
corticosteroids may improve gastrointestinal symptoms and arthritis. There is
no evidence, however, that corticosteroids, cyclophosphamide, or any other
agents are effective in the treatment of HSP-associated renal disease. Such
agents are often given to patients with more severe disease seen on renal
biopsy, such as cellular crescents, but their efficacy remains anecdotal. Plasmapheresis
has also been attempted, with limited data indicating a beneficial effect.
PROGNOSIS
After the initial episode resolves, about one third
experience bouts of disease recurrence, which are usually mild and occur during
the first several months after presentation. Patients should thus receive
careful follow-up during this period.
Most children have normal long-term renal function,
with a small fraction experiencing persistent sediment abnormalities and even
fewer experiencing renal insufficiency. In contrast, adults appear to have a
worse renal prognosis, with a large series finding that 15% experienced ongoing
moderate insufficiency, 13% developed advanced chronic kidney disease, and 10%
progressed to ESRD. Worse prognoses are more likely in those who develop more
severe renal symptoms and are found to have markers of more significant inflammation, such as cellular
crescents, on renal biopsy.
Renal transplantation can be performed on those who
have progressed to ESRD. Disease recurrence, however, occurs in up to 25% of
patients at 5 years. Although overall graft and patient survival are similar,
recurrence can be associated with graft loss, especially in patients with
necrotizing or crescentic lesions in their native kidneys.
